Abstract
Yeast Hsp104 and bacterial ClpB are ring‐forming, ATP‐dependent protein disaggregases that, together with the cognate Hsp70 system, rescue proteins from a previously aggregated state. Hsp104 possesses an N‐terminal domain, an M‐domain, and two AAA+ domains. The M‐domain is located on the Hsp104 exterior, as it is in ClpB, which was confirmed by our cryoEM structure of a functional Hsp104‐T4 lysozyme chimera. Unexpectedly, we found that our Hsp104 chimera has gained function and can solubilize heat‐aggregated proteins in the absence of the Hsp70 system. To determine the function of the M‐domain, we engineered different Hsp104 variants and chimeras, and showed that the M‐domain is essential for protein disaggregation but dispensable for the ATPase and substrate translocating activities. Remarkably, we found that replacing the yeast Hsp104 M‐domain with that of bacterial ClpB, and vice versa, switches the species‐specificity so that our chimeras now cooperate with the non‐cognate Hsp70 system. Our results demonstrate that the M‐domain controls the Hsp104 protein remodeling activities in an Hsp70‐dependent manner. This work was supported by grants from the NIH and the Welch Foundation (Q‐1530).
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